List of publications for the week of April 12, 2021
TDP-43 and PINK1 mediate CHCHD10 S59L mutation–induced defects in Drosophila and in vitro
(2021) Nature Communications, 12 (1), art. no. 1924, .
Baek, M.a , Choe, Y.-J.a , Bannwarth, S.b , Kim, J.H.a , Maitra, S.a , Dorn, G.W., IIc , Taylor, J.P.d , Paquis-Flucklinger, V.b , Kim, N.C.a
a Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, MN, United States
b Inserm U1081, CNRS UMR7284, IRCAN, Université Côte d’Azur, CHU de Nice, Nice, France
c Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, MO, United States
d Howard Hughes Medical Institute and Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States
Abstract
Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, the underlying mechanisms are unclear. Here, we generate CHCH10S59L-mutant Drosophila melanogaster and HeLa cell lines to model CHCHD10-associated ALS-FTD. The CHCHD10S59L mutation results in cell toxicity in several tissues and mitochondrial defects. CHCHD10S59L independently affects the TDP-43 and PINK1 pathways. CHCHD10S59L expression increases TDP-43 insolubility and mitochondrial translocation. Blocking TDP-43 mitochondrial translocation with a peptide inhibitor reduced CHCHD10S59L-mediated toxicity. While genetic and pharmacological modulation of PINK1 expression and activity of its substrates rescues and mitigates the CHCHD10S59L-induced phenotypes and mitochondrial defects, respectively, in both Drosophila and HeLa cells. Our findings suggest that CHCHD10S59L-induced TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways result in dominant toxicity, providing a mechanistic insight into the CHCHD10 mutations associated with ALS-FTD. © 2021, The Author(s).
Funding details
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDS1R56NS112296-01
Muscular Dystrophy AssociationMDA
Document Type: Article
Publication Stage: Final
Source: Scopus
Mitofusin activation enhances mitochondrial motility and promotes neuroregeneration in CMT2A
(2021) Neural Regeneration Research, 16 (11), pp. 2201-2203.
Dorn, G.
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
Funding details
National Institutes of HealthNIH
Document Type: Review
Publication Stage: Final
Source: Scopus
Automated Quantification of Reduced Sulcal Volume Identifies Early Brain Injury After Aneurysmal Subarachnoid Hemorrhage
(2021) Stroke, 52 (4), pp. 1380-1389.
Yuan, J.Y.a , Chen, Y.b , Kumar, A.b , Zlepper, Z.b , Jayaraman, K.a , Aung, W.Y.b , Clarke, J.V.a , Allen, M.d , Athiraman, U.c , Osbun, J.a , Zipfel, G.J.a b , Dhar, R.b
a Department of Neurosurgery (J.Y.Y., K.J., J.V.C., J.O., G.J.Z.), Washington University in St. Louis School of Medicine, St Louis, MO
b Department of Neurology (Y.C., A.K., Z.Z., W.Y.A., M.A., G.J.Z., R.D.), Washington University in St. Louis School of Medicine, St Louis, MO
c Department of Anesthesiology (U.A.), Washington University in St. Louis School of Medicine, St Louis, MO
Abstract
BACKGROUND AND PURPOSE: Early brain injury may be a more significant contributor to poor outcome after aneurysmal subarachnoid hemorrhage (aSAH) than vasospasm and delayed cerebral ischemia. However, studying this process has been hampered by lack of a means of quantifying the spectrum of injury. Global cerebral edema (GCE) is the most widely accepted manifestation of early brain injury but is currently assessed only through subjective, qualitative or semi-quantitative means. Selective sulcal volume (SSV), the CSF volume above the lateral ventricles, has been proposed as a quantitative biomarker of GCE, but is time-consuming to measure manually. Here we implement an automated algorithm to extract SSV and evaluate the age-dependent relationship of reduced SSV on early outcomes after aSAH. METHODS: We selected all adults with aSAH admitted to a single institution with imaging within 72 hours of ictus. Scans were assessed for qualitative presence of GCE. SSV was automatically segmented from serial CTs using a deep learning-based approach. Early SSV was the lowest SSV from all early scans. Modified Rankin Scale score of 4 to 6 at hospital discharge was classified as a poor outcome. RESULTS: Two hundred forty-four patients with aSAH were included. Sixty-five (27%) had GCE on admission while 24 developed it subsequently within 72 hours. Median SSV on admission was 10.7 mL but frequently decreased, with minimum early SSV being 3.0 mL (interquartile range, 0.3-11.9). Early SSV below 5 mL was highly predictive of qualitative GCE (area under receiver-operating-characteristic curve, 0.90). Reduced early SSV was an independent predictor of poor outcome, with a stronger effect in younger patients. CONCLUSIONS: Automated assessment of SSV provides an objective biomarker of GCE that can be leveraged to quantify early brain injury and dissect its impact on outcomes after aSAH. Such quantitative analysis suggests that GCE may be more impactful to younger patients with SAH.
Author Keywords
brain edema; cerebrospinal fluid; deep learning; intracranial aneurysm; subarachnoid hemorrhage
Document Type: Article
Publication Stage: Final
Source: Scopus
Long, noncoding RNA dysregulation in glioblastoma
(2021) Cancers, 13 (7), art. no. 1604, .
DeSouza, P.A.a b , Qu, X.a , Chen, H.a c , Patel, B.a , Maher, C.A.b d e f , Kim, A.H.a f
a Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
b Department of Internal Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
c Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
d Department of Biomedical Engineering, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
e McDonnell Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
f Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
Abstract
Transcription occurs across more than 70% of the human genome and more than half of currently annotated genes produce functional noncoding RNAs. Of these transcripts, the majority-long, noncoding RNAs (lncRNAs)-are greater than 200 nucleotides in length and are necessary for various roles in the cell. It is increasingly appreciated that these lncRNAs are relevant in both health and disease states, with the brain expressing the largest number of lncRNAs compared to other organs. Glioblastoma (GBM) is an aggressive, fatal brain tumor that demonstrates remarkable intratumoral heterogeneity, which has made the development of effective therapies challenging. The cooperation between genetic and epigenetic alterations drives rapid adaptation that allows therapeutic evasion and recurrence. Given the large repertoire of lncRNAs in normal brain tissue and the well-described roles of lncRNAs in molecular and cellular processes, these transcripts are important to consider in the context of GBM heterogeneity and treatment resistance. Herein, we review the general mechanisms and biological roles of lncRNAs, with a focus on GBM, as well as RNA-based therapeutics currently in development. © 2021 by the authors.
Author Keywords
Glioblastoma; Heterogeneity; LncRNA; MiRNA; Noncoding RNA; RNAi
Funding details
National Institutes of HealthNIHR01 NS051255, R01 NS094670, R01 NS106612
Foundation for Barnes-Jewish Hospital
Alvin J. Siteman Cancer Center
Document Type: Article
Publication Stage: Final
Source: Scopus
Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank
(2021) Neuro-oncology, 23 (3), pp. 356-375.
Chuntova, P.a , Chow, F.b , Watchmaker, P.B.a , Galvez, M.c , Heimberger, A.B.d , Newell, E.W.e , Diaz, A.a , DePinho, R.A.f , Li, M.O.g , Wherry, E.J.h , Mitchell, D.i , Terabe, M.j , Wainwright, D.A.k , Berzofsky, J.A.j , Herold-Mende, C.l , Heath, J.R.m , Lim, M.n , Margolin, K.A.o , Chiocca, E.A.p , Kasahara, N.a , Ellingson, B.M.q , Brown, C.E.r , Chen, Y.s , Fecci, P.E.t , Reardon, D.A.u , Dunn, G.P.v , Liau, L.M.w , Costello, J.F.a , Wick, W.x , Cloughesy, T.b , Timmer, W.C.y , Wen, P.Y.z , Prins, R.M.c aa , Platten, M.ab ac , Okada, H.a aa
a Department of Neurological Surgery, UCSF, San Francisco, CA, Mexico
b Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, Mexico
c Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, Mexico
d Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX
e Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
f Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX
g Immunology Program, Memorial Sloan Kettering Cancer CenterNY
h Department of Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
i Department of Neurosurgery, University of Florida College of Medicine, Gainesville, FL, United States
j Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
k Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, Mexico
l Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany
m Institute for Systems Biology, Seattle, WA, United States
n Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
o Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
p Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA
q Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, Mexico
r Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, California
s Department of Microbiology, Immunology & Molecular Genetics, UCLA, Los Angeles, CA, Mexico
t Department of Neurosurgery, Duke University School of Medicine, Durham, NC
u Department of Medicine/Medical Oncology, Harvard Medical School, Boston, MA
v Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
w Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, Mexico
x Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany
y Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, United States
z Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
aa Parker Institute for Cancer Immunotherapy, San Francisco, CA, Mexico
ab Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
ac DKTK CCU Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
Abstract
Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Author Keywords
clinical trial; conference report; glioblastoma; immunosuppression; immunotherapy
Document Type: Article
Publication Stage: Final
Source: Scopus
Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease
(2021) Neurology, 96 (12), pp. e1632-e1645.
Joseph-Mathurin, N., Wang, G., Kantarci, K., Jack, C.R., Jr, McDade, E., Hassenstab, J., Blazey, T.M., Gordon, B.A., Su, Y., Chen, G., Massoumzadeh, P., Hornbeck, R.C., Allegri, R.F., Ances, B.M., Berman, S.B., Brickman, A.M., Brooks, W.S., Cash, D.M., Chhatwal, J.P., Chui, H.C., Correia, S., Cruchaga, C., Farlow, M.R., Fox, N.C., Fulham, M., Ghetti, B., Graff-Radford, N.R., Johnson, K.A., Karch, C.M., Laske, C., Lee, A.K.W., Levin, J., Masters, C.L., Noble, J.M., O’Connor, A., Perrin, R.J., Preboske, G.M., Ringman, J.M., Rowe, C.C., Salloway, S., Saykin, A.J., Schofield, P.R., Shimada, H., Shoji, M., Suzuki, K., Villemagne, V.L., Xiong, C., Yakushev, I., Morris, J.C., Bateman, R.J., Benzinger, T.L.S., Dominantly Inherited Alzheimer Network
From the Departments of Radiology (N.J.-M., T.M.B., B.A.G., G.C., P.M., R.C.H., T.L.S.B.), Neurology (E.M., J.H., B.M.A., R.J.P., J.C.M., R.J.B.), Psychological and Brain Sciences (J.H.), Psychiatry (C.C., C.M.K.), and Pathology and Immunology (R.J.P.) and Division of Biostatistics (G.W., C.X.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimers Institute (Y.S.), Phoenix, AZ; Department of Cognitive Neurology and Neuropsychology (R.F.A.), Instituto de Investigaciones Neurológicas Fleni, Buenos Aires, Argentina; Departments of Neurology and Clinical and Translational Science (S.B.B.), University of Pittsburgh School of Medicine, PA; Department of Neurology (A.M.B.), Taub Institute for Research on Alzheimers Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY; Neuroscience Research Australia (W.S.B., P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales (W.S.B.), Sydney, Australia; Dementia Research Centre and UK Dementia Research Institute (D.M.C., N.C.F., A.O.), UCL Queen Square Institute of Neurology, London, UK
Abstract
OBJECTIVE: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD). METHODS: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease. RESULTS: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year). CONCLUSION: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Document Type: Article
Publication Stage: Final
Source: Scopus
Neuroscience of Object Relations in Health and Disorder: A Proposal for an Integrative Model
(2021) Frontiers in Psychology, 12, art. no. 583743, .
Svrakic, D.M.a , Zorumski, C.F.a b
a Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Recent advances in the neuroscience of episodic memory provide a framework to integrate object relations theory, a psychoanalytic model of mind development, with potential neural mechanisms. Object relations are primordial cognitive-affective units of the mind derived from survival- and safety-level experiences with caretakers during phase-sensitive periods of infancy and toddlerhood. Because these are learning experiences, their neural substrate likely involves memory, here affect-enhanced episodic memory. Inaugural object relations are encoded by the hippocampus-amygdala synaptic plasticity, and systems-consolidated by medial prefrontal cortex (mPFC). Self- and object-mental representations, extracted from these early experiences, are at first dichotomized by contradictory affects evoked by frustrating and rewarding interactions (“partial object relations”). Such affective dichotomization appears to be genetically hardwired the amygdala. Intrinsic propensity of mPFC to form schematic frameworks for episodic memories may pilot non-conscious integration of dichotomized mental representations in neonates and infants. With the emergence of working memory in toddlers, an activated self- and object-representation of a particular valence can be juxtaposed with its memorized opposites creating a balanced cognitive-affective frame (conscious “integration of object relations”). Specific events of object relations are forgotten but nevertheless profoundly influence the mental future of the individual, acting (i) as implicit schema-affect templates that regulate attentional priorities, relevance, and preferential assimilation of new information based on past experience, and (ii) as basic units of experience that are, under normal circumstances, integrated as attractors or “focal points” for interactive self-organization of functional brain networks that underlie the mind. A failure to achieve integrated object relations is predictive of poor adult emotional and social outcomes, including personality disorder. Cognitive, cellular-, and systems-neuroscience of episodic memory appear to support key postulates of object relations theory and help elucidate neural mechanisms of psychodynamic psychotherapy. Derived through the dual prism of psychoanalysis and neuroscience, the gained insights may offer new directions to enhance mental health and improve treatment of multiple forms of psychopathology. © Copyright © 2021 Svrakic and Zorumski.
Author Keywords
cognitive neuroscience; emotion-enhanced episodic memory; molecular- and systems-neuroscience; object relations; systems-consolidation of memory; trans-disciplinary integration
Document Type: Article
Publication Stage: Final
Source: Scopus
Itle: An open-source device for measuring food intake and operant behavior in rodent home-cages
(2021) eLife, 10, art. no. e66173, .
Matikainen-Ankney, B.A.a , Earnest, T.a , Ali, M.b c , Casey, E.a , Wang, J.G.d , Sutton, A.K.b , Legaria, A.A.d , Barclay, K.M.d , Murdaugh, L.B.e , Norris, M.R.d f , Chang, Y.-H.d , Nguyen, K.P.b , Lin, E.a , Reichenbach, A.h , Clarke, R.E.h , Stark, R.h , Conway, S.M.f g , Carvalho, F.i , Al-Hasani, R.f g , McCall, J.G.f g , Creed, M.C.a d g , Cazares, V.j , Buczynski, M.W.e , Krashes, M.J.b , Andrews, Z.B.h , Kravitz, A.V.a d g
a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
b National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States
c Department of Bioengineering, University of Maryland, College Park, MD, United States
d Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
e Department of Neuroscience, Virginia Polytechnic and State University, Blacksburg, VA, United States
f Center for Clinical Pharmacology, University of Health Sciences and Pharmacy, St. Louis, MO, United States
g Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
h Department of Physiology, Monash University, Clayton, Australia
i Open Ephys Production Site, Lisbon, Portugal
j Department of Psychology, Williams College, Williamstown, MA, United States
Abstract
Feeding is critical for survival and disruption in the mechanisms that govern food intake underlie disorders such as obesity and anorexia nervosa. It is important to understand both food intake and food motivation to reveal mechanisms underlying feeding disorders. Operant behavioral testing can be used to measure the motivational component to feeding, but most food intake monitoring systems do not measure operant behavior. Here, we present a new solution for monitoring both food intake and motivation in rodent home-cages: The Feeding Experimentation Device version 3 (FED3). FED3 measures food intake and operant behavior in rodent home-cages, enabling longitudinal studies of feeding behavior with minimal experimenter intervention. It has a programmable output for synchronizing behavior with optogenetic stimulation or neural recordings. Finally, FED3 design files are open-source and freely available, allowing researchers to modify FED3 to suit their needs. © 2021, eLife Sciences Publications Ltd. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Cytokine Profiling in Plasma from Patients with Brain Tumors Versus Healthy Individuals using 2 Different Multiplex Immunoassay Platforms
(2021) Biomarker Insights, 16, .
Bender, D.E.a , Schaettler, M.O.b , Sheehan, K.C.F.a c , Johanns, T.M.d e , Dunn, G.P.a b e
a Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States
e The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO, United States
Abstract
We compared the performance of two 96-well multiplex immunoassay platforms in assessing plasma cytokine concentrations in patients with glioblastoma (GBM; n = 27), individuals with melanoma, breast or lung cancer metastases to the brain (n = 17), and healthy volunteers (n = 11). Assays included a bead-based fluorescence MILLIPLEX® assay/Luminex (LMX) platform and 4 planar electrochemiluminescence kits from Meso Scale Discovery (MSD). The LMX kit evaluated 21 cytokines and the 3 MSD kits evaluated 20 cytokines in total, with 19 overlapping human cytokines between platforms (GM-CSF, IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IL-21, IL-23, MIP-1α, MIP-1β, MIP-3α, TNFα). The MSD platform had lower LLoQs (lower limits of quantification) than LMX for 17/19 cytokines, and higher LLoQs for IFN-γ and IL-21. The ULoQs were higher in LMX versus MSD assays for 17/19 shared analytes, but lower than MSD for IL-17A and IL-21. With LMX, all 19 shared analytes were quantifiable in each of 55 samples. Although MSD recombinant protein standard curves indicated lower LLoQs than LMX for most cytokines, MSD detected 7/19 (37%) native analytes in <75% of samples, including 0% detection for IL-21 and 8% for IL-23. The LMX platform categorized identical samples at greater concentrations than the MSD system for most analytes (MIP-1β the sole exception), sometimes by orders of magnitude. This mismatched quantification paradigm was supported by Bland-Altman analysis. LMX identified significantly elevated levels of 10 of 19 circulating cytokines in GBM: GM-CSF, IFN-γ, IL-1β, IL-5, IL-10, IL-17A, IL-21, IL-23, MIP-1α, and MIP-3α, consistent with prior findings and confirming the utility of applying appropriate multiplex immunoassay technologies toward developing a cytokine signature profile for GBM. © The Author(s) 2021.
Author Keywords
brain metastases; Chemokine; cytokine; detection limit; dynamic range; electrochemiluminescence; fluorescence; glioblastoma multiforme; glioma; in vitro assay; lower limit of quantification; multiplex immunoassay; performance; precision
Funding details
Merck
Document Type: Article
Publication Stage: Final
Source: Scopus
How COVID-19 Affects the Brain
(2021) JAMA Psychiatry, pp. E1-E2.
Boldrini, M.a b , Canoll, P.D.c , Klein, R.S.d e f
a Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, United States
b Department of Psychiatry, New York State Psychiatric Institute, Columbia University, Irving Medical Center, 1051 Riverside Dr, Unit 42, New York, NY 10032, United States
c Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
d Department of Medicine, Washington University, School of Medicine in St Louis, St Louis, MO, United States
e Department of Neuroscience, Washington University, School of Medicine in St Louis, St Louis, MO, United States
f Department of Pathology and Immunology, Washington University, School of Medicine in St Louis, St Louis, MO, United States
Document Type: Short Survey
Publication Stage: Article in Press
Source: Scopus
Upregulation of the pathogenic transcription factor SPI1/PU.1 in tuberous sclerosis complex and focal cortical dysplasia by oxidative stress
(2021) Brain Pathology, .
Zimmer, T.S.a , Korotkov, A.a , Zwakenberg, S.b , Jansen, F.E.c , Zwartkruis, F.J.T.b , Rensing, N.R.d , Wong, M.d , Mühlebner, A.a e , van Vliet, E.A.a f , Aronica, E.a g , Mills, J.D.a h i
a Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
b Center for Molecular Medicine, Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
c Department of Pediatric Neurology, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands
d Department of Neurology, Washington University, Saint Louis, MO, United States
e Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
f Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
g Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands
h Department of Clinical and Experimental Epilepsy, UCL, London, United Kingdom
i Chalfont Centre for Epilepsy, Chalfont St Peter, United Kingdom
Abstract
Tuberous sclerosis complex (TSC) is a congenital disorder characterized by cortical malformations and concomitant epilepsy caused by loss-of-function mutations in the mTOR suppressors TSC1 or TSC2. While the underlying molecular changes caused by mTOR activation in TSC have previously been investigated, the drivers of these transcriptional change have not been fully elucidated. A better understanding of the perturbed transcriptional regulation could lead to the identification of novel pathways for therapeutic intervention not only in TSC, but other genetic epilepsies in which mTOR activation plays a key role, such as focal cortical dysplasia 2b (FCD). Here, we analyzed RNA sequencing data from cortical tubers and a tsc2−/− zebrafish. We identified differential expression of the transcription factors (TFs) SPI1/PU.1, IRF8, GBX2, and IKZF1 of which SPI1/PU.1 and IRF8 targets were enriched among the differentially expressed genes. Furthermore, for SPI1/PU.1 these findings were conserved in TSC zebrafish model. Next, we confirmed overexpression of SPI1/PU.1 on the RNA and protein level in a separate cohort of surgically resected TSC tubers and FCD tissue, in fetal TSC tissue, and a Tsc1GFAP−/− mouse model of TSC. Subsequently, we validated the expression of SPI1/PU.1 in dysmorphic cells with mTOR activation in TSC tubers. In fetal TSC, we detected SPI1/PU.1 expression prenatally and elevated RNA Spi1 expression in Tsc1GFAP−/− mice before the development of seizures. Finally, in vitro, we identified that in astrocytes and neurons SPI1 transcription was driven by H2O2-induced oxidative stress, independent of mTOR. We identified SPI1/PU.1 as a novel TF involved in the pro-inflammatory gene expression of malformed cells in TSC and FCD 2b. This transcriptional program is activated in response to oxidative stress and already present prenatally. Importantly, SPI1/PU.1 protein appears to be strictly limited to malformed cells, as we did not find SPI1/PU.1 protein expression in mice nor in our in vitro models. © 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology
Author Keywords
brain inflammation; epilepsy; focal cortical dysplasia; mTOR; oxidative stress; tuberous sclerosis complex
Funding details
10‐02
952455
National Institutes of HealthNIHR01 NS056872
Seventh Framework ProgrammeFP7602391
Seventh Framework ProgrammeFP7
Epilepsiefonds16‐05, 20‐11
Horizon 2020642881, 722053
Document Type: Article
Publication Stage: Article in Press
Source: Scopus